The principal investigator is engaged in a long term research effort directed at understanding the physiological mechanisms which regulate the coronary circulation. This proposal describes two major projects which deal with different aspects of coronary vasoregulation in the intact dog heart. Project 1 will focus on the role of myocardial oxygen in coronary flow autoregulation. The hypothesis to be tested is that coronary autoregulation is modulated by the prevailing myocardial oxygen tension. The experimental approach will be to measure total and transmural coronary flow responses to changes in perfusion pressure following perturbations which alter the relationship between myocardial oxygen supply and demand. The left main coronary artery will be perfused from a pressure regulated reservoir. Coronary sinus oxygen tension will be used as an index of average tissue oxygen. Regional myocardial oxygen will be quantitated using a microspectrophotometric technique which measures small vessel oxygen saturation in quick frozen tissue. The degree of flow autoregulation will be corrected with coronary venous oxygen measurements. These studies will provide important information regarding the role of myocardial oxygen in the regulation of coronary resistance vessels during changes in perfusion pressure. Project 2 will focus on the role of the endothelium in modulating coronary vascular reactivity in vivo. The hypothesis to be tested is that mechanical or ischemic damage to the coronary vascular endothelium will attenuate vasodilator responses or potentiate vasoconstrictor responses to certain endogenous neurohumoral stimuli. These studies will be performed using constant pressure coronary perfusion. Epicardial coronary artery diameter will be measured using an ultrasonic dimension gauge and miniature sonomicrometer crystals attached to the outer adventitia of the artery. Dose response curves to intracoronary infusions of neurohumoral agents will be obtained before and after disruption of the endothelium. Information regarding the role of the endothelium in modulating coronary vasomotor responses will be important in better understanding the physiological control and pharmacological modulation of the coronary circulation. In addition, these studies may provide new insight into the mechanism(s) of coronary vasospasm.